Ever since mutations in the methyl-CpG binding protein 2 (MeCP2) gene were found to be the primary cause of Rett syndrome, there has been a tremendous level of interest in understanding the biology and normal function of MeCP2. The MeCP2 gene is alternatively spliced to generated two isoforms commonly referred to as MeCP2-e1 and MeCP2-e2. The significance of these two isoforms is not known and it is widely believed that there is no functional difference. Indeed, most studies in which MeCP2 is ectopically expressed do not specify which isoforms is being used, and expression studies of MeCP2 rarely distinguish between the two. We find that the two isoforms are differentially regulated in postmitotic neurons that are degenerating. Moreover, the enhanced expression of MeCP2-e2 promotes neuronal death while elevated MeCP2-e1 expression has no such effect. In addition to the differential expression pattern and effect on neuronal viability, the two isofors bind the FoxG1 with dramatically different efficiency. FoxG1 is a transcription factor which promotes neuronal survival and whose mutations have also been linked to Rett syndrome. The specific aims of the proposal are (1) to obtain a more detail understanding of MeCP2-e2-induced neurotoxicity, and (2) to define the relationship between MeCP2 and FoxG1 in the regulation of neuronal survival. Although most studies have focused on the role of MeCP2 during brain development, relatively little is known about its function in postmitotic neurons. Our results suggest that MeCP2 is involved in regulating the survival of postmitotic neurons and that the two isoforms regulate this function differently. Results from our proposed experiments will unravel the relationship between two proteins that are linked to Rett syndrome. Furthermore, they will increase existing knowledge on the regulation of neuronal death by focusing on two proteins whose role in the context of neuronal death has not been adequately studied.